PI3K/mTOR Dual Inhibitor PF-04691502 Is a Schedule-Dependent Radiosensitizer for Gastroenteropancreatic
Zeta Chow1,2, Jeremy Johnson1, Aman Chauhan1,3
1Markey Cancer Center, University of Kentucky, Lexington, KY 40536, USA.
Abstract:
Patients with advanced-stage gastroenteropancreatic neuroendocrine tumors (GEP-NETs) have a poor overall prognosis despite chemotherapy and radiotherapy (e.g., peptide receptor radionuclide therapy (PRRT)). Better treatment options are needed to improve disease regression and patient survival. The purpose of this study was to examine a new treatment strategy by combining PI3K/mTOR dual inhibition and radiotherapy. First, we assessed the efficacy of two PI3K/mTOR dual inhibitors, PF-04691502 and PKI-402, to inhibit pAkt and increase apoptosis in NET cell lines (BON and QGP-1) and patient-derived tumor spheroids as single agents or combined with radiotherapy (XRT). Treatment with PF-04691502 decreased pAkt (Ser473) expression for up to 72 h compared with the control; in contrast, decreased pAkt expression was noted for less than 24 h with PKI-402. Simultaneous treatment with PF-04691502 and XRT did not induce apoptosis in NET cells; however, the addition of PF-04691502 48 h after XRT significantly increased apoptosis compared to PF-04691502 or XRT treatment alone. Our results demonstrate that schedule-dependent administration of a PI3K/mTOR inhibitor, combined with XRT, can enhance cytotoxicity by promoting the radiosensitivity of NET cells. Moreover, our findings suggest that radiotherapy, in combination with timed PI3K/mTOR inhibition, may be a promising therapeutic regimen for patients with GEP-NET.
Insights
Combining PI3K/mTOR dual inhibition with radiotherapy enhances cancer cell death in neuroendocrine tumors. Timed administration of these treatments improves radiosensitivity and may offer a new therapeutic option for GEP-NET patients.
Area of Science:
- Oncology
- Molecular Biology
- Radiotherapy
Background:
- Advanced gastroenteropancreatic neuroendocrine tumors (GEP-NETs) have a poor prognosis.
- Current treatments like chemotherapy and radiotherapy offer limited efficacy.
- Novel therapeutic strategies are crucial for improving outcomes in GEP-NET patients.
Purpose of the Study:
- To investigate the efficacy of combining PI3K/mTOR dual inhibition with radiotherapy for GEP-NET treatment.
- To evaluate two PI3K/mTOR dual inhibitors, PF-04691502 and PKI-402, in combination with X-ray radiotherapy (XRT).
Main Methods:
- Assessed the ability of PF-04691502 and PKI-402 to inhibit pAkt and induce apoptosis in NET cell lines and patient-derived spheroids.
- Tested single-agent and combination treatments with XRT.
- Determined the impact of drug administration timing relative to XRT.
Main Results:
- PF-04691502 inhibited pAkt expression for up to 72 hours, while PKI-402 showed inhibition for less than 24 hours.
- Simultaneous PF-04691502 and XRT did not increase apoptosis.
- Administering PF-04691502 48 hours after XRT significantly enhanced apoptosis compared to single treatments.
Conclusions:
- Schedule-dependent administration of PI3K/mTOR inhibitors combined with XRT enhances cytotoxicity and radiosensitivity in GEP-NET cells.
- This combination therapy holds promise as a novel treatment regimen for advanced GEP-NET.
- Further research into timed PI3K/mTOR inhibition and radiotherapy is warranted for GEP-NET patients.
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